Therapeutic agent and process for making colloidal calcium malate



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rrnnnsrmmcaennrnnn rnocnssgron a W FQP W T *JohnTorizian, Queens Villue, N.- Y., asaignor a I L f The-DrupProducts (Jorlnci Longlsland City,"

'N.,Y.,acorporation at New 1 r a y Nonrawinli Application fleccmber 8,i1933,w i) SerlalNoJWL154 m v flhis invention rei testofa fnoverthe a euue calciumin these solutions isthus' eliminated agent and a profcess for preparing the same. -More through the kidneys within a short time; 1 particularly,"it relatestoafinew" and novel theta? After long research it;has been found that the peutic agentwhich'iscapable of intravenous and disadvantages heretofore enumerated. are defi- 15 intramuscular injection. nitely overcome itcalcium is introduced into the .5 V For some years numerous attempts have been bloodstream in the format acolloidal dispersion; made tosuccessfullyintroduce"calciunijinto -the The malic acid radical has been found tobe an streamjin order tohlleviate orfcure cer admirableivehicle for calcium injections;- It has 't ain diseases. At'thepresent time calcium isin been-iound-that, due to the slower assimilation l troduced intotheblopd'streamby direct injecby the system of the calciumion, aqueous "soluh .tion "oi." calcium salt' solutions,*niost notably," solutionsot colloidal calcium malate do not give rise tiona of calcium chloride and calcium gluconate. to tthetsudden changes; or reactions, as in the case The oi "calcium saltsior injection purposes, otthe chlorideand gluconate, which cause'pain however, has been quite limited sinceialmost in and local irritation. Because the calciuiii malate variably, suchinjections have been attended by is very finely dispersed in aqueoussolution, and 15 intense pain, discomfort and local irritation. not it is readily miscible with the normal Calcium chloride solutions, when administered blood and may, consequently, beused intrae intravenously and intramuscularly, have been venously without any untowardreaction. Due to found to be more or less irritating and frequently the enormous surface area of the fine particles of go the cause of necrosis,a most seriousalfectation colloidal calcium malate and the ready miscibility of the bones. Becauseof this serious disadvanof the solution with the bloodstream, unusual tage the use of calciumchloride solutions for in- P n ra in P w is attained, in n ea r jection purposes has found very little favor and more certain therapeutic activity in a smaller among physicians. t a r I a dosage than the .use of a larger amount of nong5 In recent yearscalciumhas been introdu d colloidal solution. Colloidal calcium malate in into the blood stream byinjection of calcium gluaqueous solutien, Of a Strength r p n in 1% conate solutions,'preterably supersaturated soluelem a calcium. has been found to be stable, n tions. The use of supersaturated calcium glubid P pi n rin und r nrdiconate solutions has apparently enjoyed a more Y- O i 3o widespread favor than havecalcium chloride sointramuscular, as Well as 1 intravenous lutions. The calcium gluconate in .thesesuperinl lnn the new Solution has pr dpa ticusaturated solutions, however, is subject to prelarly emcacious; such in t ns b in f llow d-t cipitation upon temperature change and when by 110 P irritation, necrosis Other ow d used intravenously often causes nausea and other reacti ns Th toxicity 8 l w has been P v reactions. Furthermore,intravenouslythe difierby intravenous administration in experimental 35 ence between the effective and-toxic doseseis very animals in doses 50 to 100 times the human dose smallso that extreme care must be taken in adwithout any reaction or change in the condition ministering the properdose to the patient. It has of the an ma s-X i been further found that another objection to the 1 The preferred method of e i g; this new gluconic acid radicalas avehicle for theintroduc- --aque0us s01ut10n colloidal calcium e-i 40 tion ot'calcium intothe blood stream is thatthe f s g g gl g g fg fi th usfi luconicr ra oxidize 5 0 e 0 1111 HS 00 a v elnvell fiecomes 232 3;; fjg i m t? 2:33. I is not limited thereto, the scope of the invention] acts with other ions in the blood, viz., sodium. 11 i f i f Preparing 9. Y

7 ,7 acoo so 0. a assessments:nemesis: we of w sensation is frequently caused first dissolved in 200 c. c. of water. To this solu- The calciuminth'e blood is in two formsfabout added grams swim 1 l i i hydroxidein 200 c. c. of water to form calciu in I- l n ut? 25%isndm gar I hydroxide. A dispersing medium,'such as sodium 50 solutionsot calcium chloride and calcium glui i gluconate, isthen added to the above mixture. conate the calcium is in the diffused form; This In this particulafexample; a solution of grams of anhydrous sodium glucona'te in 200 c. c. of

I me llel e.v 37 t a 1 vwaterihas been found suitable. A solution of 20 r 55 cartilag'eaw er he calei is a grams of malic acidin 200c. c. of water is then 55 'tions may be made in the present invention withsolution of the desired concentration of calcium.

In this particular example, enough water is added The completed solution is then filtered through a filter having a porosity of about 100 microns, thus permitting the solution to I to make up 1,000 c. c.

pass through without afiecting the colloidal properties of the calcium malate. Previously washed and sterilized ampuls of approximately 5 c. cJsize are thenpromptly filled with the solution andth'e filled ampuls sealed and sterilized at 100C. for about 45 minutesi 'I' I On analysis, each 50. c. of the finished solution isffound to contain 0.05 grams of finely dispersed,

colloidal elemental calcium (in the form of malate) which is considered to bethe average dose. Through the ultramicroscope the solution demonstrates active. and prolonged Brownian movement. I v

It is obvious that various changes and modificaout departing from the spirit thereof, the scope of the invention being limited only by the following claims.

What is claimed is:

1. As a new therapeutic agent for injection purposes calciummalate finely dispersed in aqueous solution. 7 r

2. As a newtherapeutic agent for injection purposes calcium malate in true colloidal solution having a pH value of substantially-8.5.

-3. As a-new therapeutic agent for injection purposes calcium' malate in true colloidal solution *having an effective calcium content of approximately .01 gram per 1c. c. of solution. 4. As a new therapeutic agent for injection purposes calcium malate in true colloidal solution having. an effective calcium content of approximately .01 'gramper 1 c. c. of solution and having a pH value of "substantially 8.5.

'5. As a new therapeutic agent for injection purposes-calcium malate in true colloidal'solution and a dispersing agent.

6. The product of claim 5 in which the dispersing agent issodium gluconate.

I 7. 1A process-for preparing an aqueous solution of colloidal. calcium malate comprising reacting calcium chloride withsodium hydroxide, adding sodium gluconate and then adding thereto malic acid.

I 8.-A process for preparing an aqueous solution of, colloidal calcium malate comprising precipitating calcium hydroxide, adding a dispersing .agent, adding to this reaction mass malic' acid,

adjusting the pH of the solution to substantially 3.5. and thenaddingsufficient water so that the resultant solution contains approximately .01 gram of calcium per 1 c. c. of solution.

JOHN TORIGIAN, 

